Ischemia-Induced Neural Stem/Progenitor Cells in the Pia Mater Following Cortical Infarction

Abstract

Increasing evidence shows that neural stem/progenitor cells (NSPCs) can be activated in the nonconventional neurogenic zones such as the cortex following ischemic stroke. However, the precise origin, identity, and subtypes of the ischemia-induced NSPCs (iNSPCs), which can contribute to cortical neurogenesis, is currently still unclear. In our present study, using an adult mouse cortical infarction model, we found that the leptomeninges (pia mater), which is widely distributed within and closely associated with blood vessels as microvascular pericytes/perivascular cells throughout central nervous system (CNS), have NSPC activity in response to ischemia and can generate neurons. These observations indicate that microvascular pericytes residing near blood vessels that are distributed from the leptomeninges to the cortex are potential sources of iNSPCs for neurogenesis following cortical infarction. In addition, our results propose a novel concept that the leptomeninges, which cover the entire brain, have an important role in CNS restoration following brain injury such as stroke.

Pericytes, mesenchymal stem cells and their contributions to tissue repair

“…Activated pericytes have been shown to detach from local capillaries, migrate to the site of injury and differentiate into myofibroblasts (Goritz et al, 2011;Lin et al, 2011;Ren et al, 2013). However, the recruitment of pericytes following injury and their collagen-producing capacity may be dependent on both the type of injury and the tissue under investigation (Birbrair et al, 2014a;Nakagomi et al, 2011). Activated pericytes have been shown to upregulate genes associated with migration, for example ADAMTS1 and TIMP3 (Hung et al, 2013;Schrimpf et al, 2012).…”

Leptomeninges: a novel stem cell niche with neurogenic potential

“…The leptomeninges are histologically continuous with the cortical parenchyma along the blood vessels and are located at a perivascular niche as vascular pericytes (7). We showed that leptomeningeal nestin + cells spread into the cortical parenchyma, localized near CD31 + endothelial cells, and expressed pericytic makers such as PDGFRβ and NG2 (5). Although the functions of pericytes remain unclear, it has been well-documented that pericytes in various organs, including the CNS, have multipotent stem cell activity (8).…”

“…These findings showed that leptomeningeal NSPCs have potential to contribute to cortical neurogenesis during early developmental stages. Using adult mice following ischemic stroke, we previously showed that nestin + ischemia-induced NSPCs (iNSPCs) were present in the leptomeninges of ischemic areas, and they were not observed in the leptomeninges of nonischemic areas (5). Leptomeningeal cells isolated from ischemic areas produce neurosphere-like cell clusters that give rise to neural cells, including neurons (5).…”

“…O f n o t e , u s i n g s i n g l e -c e l l transcriptomics, they also showed that leptomeningeal PDGFRβ + cells generate various types of clusters that exhibited features of pericytic/fibroblastic, endothelial, and microglial lineages in addition to radial glia-like lineages. However, we recently showed that PDGFRβ + pericytes isolated from post-stroke areas, including the leptomeninges, exhibited multipotent stem cell activity and that they give rise to not only neural (e.g., neurons) but also vascular lineages (e.g., endothelial cells and microglia) (11,12 (5,6,19,20). Thus, the leptomeninges should become a new target for treating CNS developmental disorders and diseases.…”

Intermediate filament protein nestin is expressed in developing meninges

“…Meninges in the brain and spinal cord may also directly harbor stem cells under basal conditions (8) and in response to insults, such as stroke and spinal cord injury (9,10). Thus, the meninges regulate the development of the brain and may also harbor stem cells in adult brain.…”